P256	Different intracellular pathways triggered by the selective FLT-1-agonist PLGF in vascular smooth muscle cells exposed to hypoxia.
A.Parenti, L.Bellik, M.C.Vinci, S.Filippi, F.Ledda
Department of Pharmacology, University of Florence, Florence, IT.

Proliferation and migration of activated vascular smooth muscle cells (VSMCs) are fundamental events involved in vascular wall remodelling. We previously demonstrated that hypoxia makes VSMCs responsive to Placental Growth Factor (PlGF) through the induction of functional Flt-1 receptors. We now investigate the molecular mechanisms involved in the effect of PlGF on proliferation and contraction of VSMCs previously exposed to hypoxia (3% O2). In cultured rat VSMCs treated with hypoxia, PlGF increases the phosphorylation of Akt, MAPK-p38 and STAT-3, STAT-3 activation being higher than that of other kinases. In agreement with this finding, the proliferation of hypoxia-treated VSMCs in response to PlGF was significantly impaired by the MAPK-p38 inhibitor SB202190 and the PI3K inhibitor LY 294002, but was almost completely prevented by AG 490, a JAK/STAT inhibitor. Since hypoxia reversed the vasorelaxant effect of PlGF into a vasoconstrictor response, the mechanism of this effect was also investigated. Significant Flt-1 activity was measured in preparations exposed to hypoxia. Inhibitors of MEK, Akt and STAT-3 induced a modest inhibition of the PlGF-evoked vasoconstriction, while SB202190 markedly impaired the PlGF-induced contractile response. These data represent the first evidence that different intracellular signaling induced by Flt-1 receptor activation in VSMCs may be responsible for diverse biological effects: while MAPK-p38 is involved in vasoconstriction, JAK/STAT-3 and ERK1/2 activation leads to VSMC proliferation. These findings may highlight the role of PlGF in vascular pathology.

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